A2 Bio’s Trial for Solid Tumor Tmod CAR-T A2B694 Doses First Patient

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A2B694 is being evaluated for the treatment of patients with mesothelin-expressing solid tumors that have lost HLA-A*02 expression.

The first patient has been dosed in A2 Biotherapeutics (A2 Bio)’s phase 1/2 EVEREST-2 clinical trial (NCT06051695) evaluating A2B694, an investigational logic-gated Tmod chimeric antigen receptor T-cell (CAR-T) therapy, in patients with mesothelin (MSLN)-expressing solid tumors that have lost HLA-A*02 expression.1

EVEREST-2 is recruiting patients with solid tumors with MSLN-expression, including lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, and mesothelioma cancers. Patients must have previously participated in the company’s BASECAMP-1 screening study (NCT04981119) that is identifying patients with solid tumors that are positive for somatic human leukocyte antigen (HLA)-A*02 loss of heterozygosity (LOH).2 The Tmod approach is intended to allow the CAR-T to selectively kill tumor cells while sparing healthy tissue by conferring the CAR T-cells with an “activator” that targets MSLN and a “blocker” that protects cells that do not have HLA-A*02 LOH.1

“Dosing our first patient in this trial is a key step to provide a precise, novel CAR-T therapy to patients with solid tumors that express mesothelin with no curative treatment options,” William Go, MD, PhD, the chief medical officer of A2 Bio, said in a statement.1 “Sadly, current treatment options for these patients are palliative and limited by toxicity in the recurrent, unresectable, locally advanced or metastatic setting. All of us at A2 Bio would like to thank participating patients, investigators, and clinical care providers.”

A2B694 is 1 of 2 Tmod CAR-T therapy products that A2 Bio currently has in clinical development. The other is A2B530, which features the same blocker as A2B694 but has an activator targeting carcinoembryonic antigen (CEA). A2B530 is currently being evaluated in the first-in-human, multicenter phase 1/2 EVEREST-1 clinical trial (NCT05736731), which dosed its first patient in May 2023.3 EVEREST-1 is recruiting patients with pancreatic, colorectal, lung, and other solid cancers that express CEA and have HLA-A*02 LOH.

Similar to EVEREST-2, EVEREST-1 is only recruiting patients who previously participated in BASECAMP-1. Notably, apheresis is performed on participants in BASECAMP-1 to collect and store their T-cells. Upon disease progression, those who meet eligibility requirements may be screened for EVEREST-1, and have their T-cells used to produce A2B530 for administration in EVEREST-1.

Last year, CGTLive® spoke to Ben Creelan, MD, a medical oncologist at Moffitt Cancer Center who specializes in the treatment of lung cancer and in oncology cell therapy research, about novel cell therapy approaches in solid tumors. During the discussion, he spoke about A2 Bio’s Tmod approach.

“In the case of the A2 Bio approach, they're targeting CEA, a marker which showed excellent responses back a decade ago or more, but too much toxicity—too much colitis,” Creelan said in the interview. “By having that logic switch, they're hoping to get rid of the colitis—get rid of the toxicity—and still maintain that tumor potency. And that's not the only marker; they have an entire pipeline building off of this going against other HLA types and, more importantly, other markers like MSLN, another notoriously difficult marker to target in-clinic because of the incidence of pleuritis, peritonitis, and pneumonitis, which affect all the sorts of tissues that normally express MSLN. By having a CAR against MSLN that has that off-switch—it still remains to be seen how well that will work in patients—but at least the preclinical data is fairly convincing when you see their tumor confluence assays. When they compared normal CAR to their CAR, the specificity looked pretty good.”

REFERENCES
1. A2 Bio announces first patient dosed in EVEREST-2 phase 1 clinical trial of novel mesothelin logic-gated CAR T. News release. A2 Biotherapeutics, Inc. May 16, 2024. Accessed May 19, 2024. https://www.a2bio.com/a2-bio-announces-first-patient-dosed-in-everest-2-phase-1-clinical-trial-of-novel-mesothelin-logic-gated-car-t/
2. Simeone DM, Hecht JR, Smith C, et al. BASECAMP-1: A master prescreening study to identify patients with high-risk or metastatic solid tumors with HLA loss of heterozygosity (LOH) in preparation for TmodCAR T-cell therapy trials. Presented at: SITC 38th Annual Meeting, held November 1-5, 2022, in San Diego, California. Abstract #636
3. A2 Bio announces first patient dosed in phase 1 clinical trial of A2B530, a novel cell therapy for the treatment of colorectal, pancreatic, and non-small cell lung cancers. News release. A2 Biotherapeutics, Inc. May 30, 2023. Accessed June 1, 2023. https://www.a2bio.com/a2-bio-announces-first-patient-dosed-in-phase-1-clinical-trial-of-a2b530-a-novel-cell-therapy-for-the-treatment-of-colorectal-pancreatic-and-non-small-cell-lung-cancers/
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